Traumatic brain injury (TBI) is initiated by a physical deformation to the brain tissue and often results in dysfunction or death. Previously, researchers have devoted substantial attention to the initial disruption in [Ca2+]i homeostasis. However, recent data from ischemic and excitotoxic injury models suggest that alterations in [CI-]i may also profoundly impact neuronal function. Neuronal [CI-]i is regulated by cation-chloride transporters that either accumulate (NKCC1) or extrude (KCC2) chloride. Alterations in [CI-]i can cause reduced inhibition, due to excitatory function of the primary inhibitory neurotransmitter, GABA. I hypothesize that TBI causes an immediate influx of [CI-]i through altered membrane permeability, resulting in GABA excitation. The enhanced [CI-]i will result in reduced KCC2 and enhanced NKCC1 expression in the post-acute phase (12-24 hrs) of TBI, resulting in long-term loss of inhibition. I propose to evaluate this hypothesis using an in vitro model of TBI where neurons are cultured on a flexible silicone membrane and subjected a rapid pressure pulse. Understanding the mechanism of injury induced [CI-]I alterations will aid in the development of better treatments for post-traumatic seizures.